The overarching aim of this application is to greatly expand knowledge about preclinical AD and specifically to characterize the chronology of biomarker changes, determine their path biological signatures (if any), and identify cognitively normal persons who are at very high risk for developing symptomatic AD. Successful treatment strategies will require biomarkers that can identify individuals at high risk for AD and at the earliest clinical stages in order to target them for clinical trials, disease- modifying therapies nd to monitor therapy success. The overall Specific Aims in this renewal application are to: 1. Follow the current participants in ACS and add new enrollees to maintain the sample size at ~300. 2. Obtain longitudinal data from the ACS participants at 2 year intervals with the following measures: a. Clinical and cognitive assessments (Clinical Core) b. Amyloid imaging with PET PIB (Project 1) c. Assays of amyloid-beta (A[unreadable]), tau, phosphorylated tau181 (p- tau181), and novel analytes in CSF and blood (Project 2, supported by the Biomarker Core) d. Attentional control battery and task-related functional MRI (fMRI) (Project 3) e. Structural MRI, resting state functional connectivity MRI (fcMRI), diffusion tensor imaging (DTI), and cerebral blood flow using arterial spin labeling (ASL) (Project 4) 3. Analyze associations among rates of change of all disease markers from all Cores and Projects (Data Management and Biostatistics Core). PUBLIC HEALTH RELEVANCE: The results of clinical assessment, studies of biomarkers (PET imaging, MRI of the brain, cerebrospinal fluid analysis, and tasks which place a high load on attentional systems) will be correlated to identify the earliest brain changes of AD, determine the evolution of these changes over time, and assess their predictive power for the eventual development of symptomatic AD by studying participants in two groups-one with a family history of AD and the other with no family history of AD. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATION;Dr. John C. Morris, Core Leader (CL) DESCRIPTION ( provided by applicant): The Administration Core acts to ensure that the research and programmatic goals of the Adult Children Study program project grant (ACS PPG) are met. The administrative leadership consists of the Director (Morris) and the Executive Director (Buckles). They are assisted by the Executive Committee that includes these individuals, leaders of Cores and Projects, and other senior faculty. The Administration Core supports, monitors, and coordinates the activities of all components of the ACS PPG. It will annually convene an External Advisory Committee to review activities and progress. The specific aims are to: 1. Coordinate and integrate the Cores and Projects and provide administrative and budgetary support and oversight, ensuring appropriate utilization of funds 2. Monitor the effectiveness of the PPG toward achieving the stated goals 3. Arrange for periodic external review and advice concerning PPG goals and progress 4. Coordinate and oversee data integration with Washington University Center for Biomedical Informatics to develop, maintain, and monitor an integrated database PUBLIC HEALTH RELEVANCE: The Administration Core ensures that goals of the Adult Children Study (ACS) are met, including identifying the earliest brain changes of AD, determining the evolution of these changes overtime, and assessing their predictive power for the eventual development of symptomatic AD. With the assistance of an External Advisory Committee and an Executive Committee including the leaders of the Projects and Cores, the Administration Core supports, monitors, and coordinates the activities of all components of the ACS.